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Hurskainen R, Teperi J, Rissanen P, et al. Clinical Outcomes and Costs With the Levonorgestrel-Releasing Intrauterine System or Hysterectomy for Treatment of Menorrhagia: Randomized Trial 5-Year Follow-up. JAMA. 2004;291(12):1456–1463. doi:10.1001/jama.291.12.1456
Author Affiliations: Departments of Obstetrics and Gynecology, University of Helsinki (Drs Hurskainen and Paavonen), University of Turku (Dr Grenman), University of Oulu (Dr Kivelä), University of Tampere (Dr Kujansuu), and University of Kuopio (Dr Yliskoski); School of Public Health, University of Tampere (Dr Rissanen); and STAKES (National Research and Development Center for Welfare and Health), Helsinki (Drs Hurskainen, Teperi, Aalto, and Vuorma), Finland.
Context Because menorrhagia is often a reason for seeking medical attention,
it is important to consider outcomes and costs associated with alternative
treatment modalities. Both the levonorgestrel-releasing intrauterine system
(LNG-IUS) and hysterectomy have proven effective for treatment of menorrhagia
but there are no long-term comparative studies measuring cost and quality
Objective To compare outcomes, quality-of-life issues, and costs of the LNG-IUS
vs hysterectomy in the treatment of menorrhagia.
Design, Setting, and Participants Randomized controlled trial conducted between October 1, 1994, and October
6, 2002, and enrolling 236 women (mean [SD] age, 43 [3.4] years) referred
to 5 university hospitals in Finland for complaints of menorrhagia.
Interventions Participants were randomly assigned to treatment with the LNG-IUS (n
= 119) or hysterectomy (n = 117) and were monitored for 5 years.
Main Outcome Measures Health-related quality of life (HRQL) as measured by the 5-Dimensional
EuroQol and the RAND 36-Item Short-Form Health Survey, other measures of psychosocial
well-being (anxiety, depression, and sexual function), and costs.
Results After 5 years of follow-up, 232 women (99%) were analyzed for the primary
outcomes. The 2 groups did not differ substantially in terms of HRQL or psychosocial
well-being. Although 50 (42%) of the women assigned to the LNG-IUS group eventually
underwent hysterectomy, the discounted direct and indirect costs in the LNG-IUS
group ($2817 [95% confidence interval, $2222-$3530] per participant) remained
substantially lower than in the hysterectomy group ($4660 [95% confidence
interval, $4014-$5180]). Satisfaction with treatment was similar in both groups.
Conclusions By providing improvement in HRQL at relatively low cost, the LNG-IUS
may offer a wider availability of choices for the patient and may decrease
costs due to interventions involving surgery.
Menorrhagia is an important cause of ill health in women worldwide.
About one third of women report heavy menstrual bleeding at some time in their
lives.1 Menorrhagia is the presenting symptom
among the majority of women who undergo hysterectomy,2,3 and
recent data suggest that menorrhagia is an increasingly common health problem.4
The levonorgestrel-releasing intrauterine system (LNG-IUS) (Schering
Co, Turku, Finland) has been advocated for the treatment of menorrhagia as
an alternative to surgery.5 The LNG-IUS is
an intrauterine system that releases 20 µg of levonorgestrel every 24
hours over 5 years. The LNG-IUS was developed during the 1980s and licensed
first for contraception in Finland in 1990. The estimated number of current
LNG-IUS users worldwide is more than 4 million, in approximately 100 countries.
In many countries the LNG-IUS is licensed both for contraception and treatment
of menorrhagia. In the United States, the system is so far approved for contraception
only (Tarja J. Butzow, MD, PhD, Schering Co, Finland, written communication,
December 17, 2003).
Studies of hysterectomy, endometrial ablation, and the LNG-IUS have
raised important questions about health outcomes and the allocation of resources
for treatment of menorrhagia. Hysterectomy is effective but can be associated
with complications and costs. Endometrial ablation may be an alternative to
hysterectomy for the short term, but its benefit lessens over time.6 The LNG-IUS is an effective and reversible treatment
modality for menorrhagia. The LNG-IUS reduces menstrual blood loss (MBL) more
than tranexamic acid,7 nonsteroidal anti-inflammatory
drugs,8 danazol,8 oral
progestogens,8 combined oral contraceptives,8 or long-term norethisterone.9 No
difference in patient satisfaction or health-related quality of life (HRQL)
has been found between the LNG-IUS and endometrial destruction, and both are
effective in reducing MBL.10,11 The
LNG-IUS also reduced the preference for hysterectomy.5 We
have shown that the LNG-IUS is more cost-effective than hysterectomy after
1 year of follow-up.12 Whether there is a longer-term
advantage is unknown.
We conducted a randomized trial of the LNG-IUS and hysterectomy for
the treatment of menorrhagia and report herein the clinical findings, quality-of-life
outcomes, and costs after 5 years of follow-up.
Full details of the original trial have been reported elsewhere.12 Briefly, each woman who participated had been referred
by a general practitioner or gynecologist for complaints of menorrhagia to
1 of the 5 university hospitals in Finland between October 1, 1994, and September
10, 1997. Overall, 236 women aged 35 to 49 years who were menstruating, had
completed their desired family size, and were eligible for both treatments
were randomized to receive the LNG-IUS (n = 119) or hysterectomy (n = 117)
(Figure 1). The randomization was
performed separately for each center on randomly varying clusters using numbered,
opaque, and sealed envelopes. The follow-up visits took place 6 months and
12 months after the treatment, and again 5 years after the randomization.
For women having hysterectomy, there was a planned visit 4 weeks after hysterectomy.
Questionnaires were completed by participants and study gynecologists at baseline
before randomization and at each follow-up visit. Participants completed a
questionnaire at home containing HRQL instruments and questions on health
care use, sick leave days, and travel costs separately for menorrhagia and
other conditions. Gynecologists completed a form that included questions on
participant menstrual problems, LNG-IUS–associated bleeding and reasons
for discontinuing its use, operation details, and complications, as well as
The ethics committees of all the university hospitals and STAKES (National
Research and Development Center for Welfare and Health) approved the study.
All participants provided written informed consent.
The 5-Dimensional EuroQol (EQ-5D)13,14 was
chosen as the primary measure of effectiveness because it provides a single
numeric score for HRQL, is universally used, and has undergone validation
in the Finnish general population.15 The EQ-5D
consists of five 3-level subscales that indicate dimensions of mobility, self-care,
usual activities, pain, and mood. The EQ-5D score index, which ranges from
0 to 1, was calculated by using relative weights for subscales obtained from
a Finnish population survey.15 Better HRQL
is indicated by higher scores. A validated Finnish version of the RAND 36-Item
Short-Form Health Survey (RAND-36)16,17 was
also used for measurement of HRQL. The RAND-36 survey is composed of 8 multi-item
dimensions: general health, physical functioning, mental health, social functioning,
energy, pain, and physical and emotional role functioning. There is a range
from 0 to 100 in each subscale, with higher scores indicating better HRQL.
General health was assessed using a visual analog scale (scale range, 0-100).
Measurement of anxiety was accomplished using the validated Finnish
version of the Spielberger 20-Item State-Trait Anxiety Inventory, with a range
of 20 to 80.18 Measurement of depression was
accomplished using the 13-item version of the Beck Depression Inventory, with
a scale of 0 to 39.19 For both scales, higher
scores are indicative of more symptoms. Sexuality-related elements were evaluated
using the McCoy Sex Scale as modified by Wiklund.20,21 This
scale contains 3 subscales: sexual satisfaction (5 items; subscale range,
5-35), sexual problems (2 items; subscale range, 2-14), and participant satisfaction
with the partner (3 items; subscale range, 3-21).
Overall satisfaction with the treatment was assessed by a 5-level question
(from very unsatisfied to very satisfied). This assessment approach has been
Data on direct costs including use of hospital services (operations,
inpatient days, procedures, and outpatient visits) and medication, and on
indirect costs including sick leave days as productivity losses, were obtained
from medical records and the questionnaires. Information was obtained from
the questionnaires for Papanicolaou tests, physician appointments out of hospital
related to menorrhagia, and out-of-pocket costs due to menorrhagia (all direct
costs) during the first and the last study years.
A system of pricing based on diagnosis related groups in use at Helsinki
University Hospital was used to determine prices of hospital procedures. The
first-year costs were based on 1996 price levels, and the annual costs thereafter
on 2001 price levels. Hysterectomy unit cost comprised 1 preoperative visit,
the operation itself, and 1 to 5 inpatient days ($1864 in 1996 and $2055 in
2001). If a longer hospital stay was required, the additional days were priced
according to the average bed day price ($247 and $297, respectively) for the
university hospital. Primary health care service costs were calculated from
the unit costs of these services in the Helsinki Occupational Health Care
Centers. The definition of the production loss cost per sick leave day was
an average daily gross wage for women in Finland, which included social security
contributions ($71 and $85). The costs were discounted by the commonly recommended
rate of 3% per year23 to 1996 (average year
for treatment decisions). The currency conversion had its basis in purchasing
power parities in 1996 (US $1 = FIM 5.89).24
The uncertainty relating to analytical methods was handled by performing
sensitivity analyses. Discounting was also performed using another commonly
used rate of 5%.23 Because of difficulties
in measuring costs of production loss properly, a sensitivity analysis using
a lower estimate of production loss (one third of the average wage rate)25 was also performed. Checking the questionnaires and
subsequently the medical records to double-check information provided in the
questionnaires produced comprehensive data on costs for the 5 study years.
Only the costs of Papanicolaou tests, physician appointments out of hospital
related to menorrhagia, and out-of-pocket costs due to menorrhagia during
years 2 to 4 were uncertain and had to be specified. To address this uncertainty,
the following sensitivity analysis was performed. To calculate costs for years
2 through 4, cost data were taken from questionnaires for the last year in
both groups. The data were used to calculate an average cost, which was then
multiplied by 4 and added to the cost for the first year. This summary figure
was used as the estimated costs of Papanicolaou tests, physician appointments
out of hospital related to menorrhagia, and out-of-pocket costs due to menorrhagia
for all 5 years. This approach provides a good estimate of actual costs because
the first-year cost is likely different from the others and costs for the
subsequent 4 years are likely to be similar. These costs were marginal, only
1% to 4% of total costs. None of the 4 women lost to follow-up during this
period underwent gynecological surgery, as ascertained by checking the Finnish
Hospital Discharge Register for intercurrent surgeries. Because of different
pricing systems applied in other countries, we also performed a sensitivity
analysis with 2 different hysterectomy prices (80% of the base case and hysterectomy
price in the United States in 199626).
Measurement of MBL occurred before randomization and after 12 months
(reported previously12) and 5 years. Menstrual
blood loss was measured using the alkaline hematin method27 and
was calculated as the average total for the duration of the participant's
menstrual period. Blood hemoglobin concentrations were measured using a Coulter
Counter T660 (Coulter Electronics Ltd, London, England). Serum ferritin was
measured by a direct chemiluminescent immunoassay method (Chiron Diagnostics,
Halsteed, England). The blood samples were drawn during period days 1 to 7.
The target of 115 patients in each treatment group was based on power
calculation. Based on an EQ-5D standard deviation (SD) of 19 percentage points
(as per an analysis including a Finnish 34- to 49-year-old female population15) and an α level of .05, the study had 80% power
to detect a between-group difference of 7.5 percentage points. There was a
mean of 5% missing data for HRQL measurement, which was treated in the analysis
as follows. For the EQ-5D, if responses on fewer than 3 dimensions were missing,
a mean value for the nonmissing responses was used; otherwise, the scale was
coded as missing. For the RAND-36 scales having dimensions with 4 or more
items, missing data were handled by computing an individual mean value of
the nonmissing responses for those having responded to at least 50% of the
scale items. Otherwise, the total scale was coded as missing. For the RAND-36
scales having dimensions with fewer than 4 items, no missing values were allowed
(ie, the scale was coded as missing). For the general health assessment via
visual analog scale, there was also a mean of 5% missing data, for which a
mean value for the nonmissing responses was used. For the Spielberger, Beck,
and McCoy questionnaires, there was a mean of 9% missing data and the individual
mean was used if less than one third of the items were missing; otherwise,
the scale was coded as missing. Using these adjustments, the means for the
individual participants were used to handle the missing data except in 1%,
for whom group means were used because of the extent of the missing data.
If not indicated otherwise, all analyses were performed according to the intention-to-treat
principle. Changes in outcome measures within the groups were tested by the
paired-sample t test and differences in score changes
between the groups were tested by the t test for
independent samples. The Wilcoxon signed rank test was used for testing the
baseline scores for the subgroup analyses. All analyses were performed using
SAS version 8.2 (SAS Institute Inc, Cary, NC). Probability values ≤.05
were considered statistically significant.
The study was conducted between October 1, 1994, and October 6, 2002.
At baseline, the mean age of the 236 participants was 43 years (SD, 3.4),
parity was 2.1 (SD, 1.1), and body mass index calculated as weight in kilograms
divided by the square of height in meters was 25.8 (SD, 4.8) (some characteristics
have been reported previously and some outcomes given herein include 1-year
outcomes from that prior report12). Of 234
women reporting, 99 (with similar distribution between randomization groups)
indicated having some medical treatment for menorrhagia in the prior 6 months
and 135 reported having none. After 5 years of follow-up, 232 women (99%)
of mean age 48 years (SD, 3.3) were analyzed for the main outcome measures.
Overall satisfaction with the treatments was high; 94% of the women in the
LNG-IUS group and 93% of the women in the hysterectomy group were satisfied
or very satisfied.
Of the 119 women randomized to treatment with the LNG-IUS, insertion
of the intrauterine system could not be achieved in 2 women, 1 having cervical
stricture and 1 having submucosal fibroid identified during the randomization
visit. Of all women, 115 (97%) attended the 5-year follow-up, and 2 (2%) mailed
the questionnaire without having a physical examination. Two (2%) women were
lost to follow-up.
Five years after randomization, 57 (48%) women (of whom 8 had a replacement
LNG-IUS) had the LNG-IUS in situ and 10 (8%) were without LNG-IUS (of whom
1 had had thermoablation). Hysterectomy had been performed in 50 women (42%)
(12 vaginally, 8 abdominally, and 30 laparoscopically, including bilateral
oophorectomy in 6). Overall, 8 women underwent bilateral oophorectomy and
4 underwent unilateral oophorectomy. Fifteen (30%) of these 50 women developed
complications, including postoperative pelvic infection (9), strong abdominal
pains (3), wound infection (2), heavy perioperative bleeding (1), intestinal
occlusion (1), postoperative bleeding (1), postoperative fever (1), and urinary
Of the 57 women with the LNG-IUS in situ, 43 (75%) reported amenorrhea
or oligomenorrhea, 11 (19%) reported irregular bleeding, and 3 (6%) reported
scanty regular bleeding. The mean MBL (measured for only 4 women) was 17 mL
(SD, 11.3; range, 8-32 mL). The rest of the women with the LNG-IUS had amenorrhea
or only minimal spotting. Among the 60 women who did not continue treatment
with the LNG-IUS, 42 (70%) reported intermenstrual bleeding; 19 (32%), heavy
bleeding; and 18 (30%), hormonal symptoms (some had more than 1 complaint)
for the reason of the removal of the LNG-IUS. Six women developed lower abdominal
pain, 2 of whom were eventually found to have diverticulosis. Two women had
the LNG-IUS removed after developing depression, 1 because of recurrent thromboembolic
disease, and 1 because of benign ovarian cyst. One woman wanted hysterectomy
without any specific indication. No participant discontinued the intervention
because of menopause.
Of the 117 women randomized to the hysterectomy group, 114 completed
the 5-year follow-up, and 1 mailed the questionnaire without having a physical
examination. One woman died in 2000 in a car crash. Only 1 woman withdrew
from the study. Of the 117 women, 109 underwent hysterectomy, including 2
who had the surgery 12 months after randomization. Two women had the LNG-IUS
inserted after randomization. Five women had cancelled their operation following
reduced MBL or because of a job or family situation.
The hysterectomy was performed vaginally in 30 (28%) women, abdominally
in 22 (20%), and laparoscopically in 57 (52%). Bilateral oophorectomy was
performed in 5 cases. Overall, 7 women underwent bilateral oophorectomy and
5 underwent unilateral oophorectomy. Three bladder perforations and 1 bowel
perforation were included in intraoperative complications. Postoperative complications
occurred in 33 (30%) women, including wound infection (12), infected pelvic
hematoma (6), urinary retention (4), severe abdominal pain (3), ileus (2),
postoperative bleeding (2), postoperative fever (2), wound rupture (2), peritonitis
(1), ureter lesion (1), and vesicovaginal fistula (1).
Scores on the EQ-5D were improved in both groups compared with baseline
values (LNG-IUS group, P = .002; hysterectomy group, P = .001), with no substantial difference between the groups
In both groups, HRQL measured by the RAND-36 questionnaire improved
significantly in all dimensions (P<.01) except
physical functioning (LNG-IUS group, P = .40; hysterectomy
group, P = .30), with no substantial differences
between the groups.
General health status, as measured by visual analog scale, was significantly
improved (P = .04) in the hysterectomy group but
not in the LNG-IUS group (P = .08), with no substantial
difference between the groups. The anxiety (P = .001
in both groups) and depression scores (LNG-IUS group, P = .006; hysterectomy group, P = .001) improved
significantly, with no substantial difference between the groups. Sexual function
scores showed no substantial within- or between-group changes, except that
participant satisfaction with the partner declined in the LNG-IUS group (P = .006).
In a subgroup analysis of the LNG-IUS, the baseline RAND-36 scores for
those having hysterectomy by 5 years were lower in 6 of 8 dimensions compared
with those having the LNG-IUS in situ (general health, P = .02; physical functioning, P = .01; social
functioning, P = .004; energy, P = .009; pain, P<.001; and physical role
functioning, P = .006). The depression score was
higher (P = .02). The follow-up score changes did
not differ substantially. Similarly, the baseline scores for those in the
LNG-IUS group undergoing hysterectomy compared with those in the hysterectomy
group were lower in 6 dimensions (general health, P =
.03; mental health, P = .05; social functioning, P = .003; energy, P = .02; pain, P = .02; and physical role functioning, P = .04). The anxiety (P = .03) and depression
scores (P = .01) were higher. The follow-up score
changes did not differ substantially. Of note, these subanalyses are not based
on intention-to-treat; thus, the evidence may be less robust than the other
Menstrual blood loss was measured in 227 women at baseline; objective
menorrhagia (ie, MBL ≥80 mL) was present in 132 (58%) women. The mean MBL
was 130 mL (SD, 116) in the LNG-IUS group and 128 mL (SD, 116) in the hysterectomy
group. At 5 years, only 4 of 57 women with LNG-IUS in situ who had bleeding
(out of 11 having irregular bleeding and 3 having regular scanty bleeding)
contributed samples for MBL. All the other women had only minimal spotting.
Blood hemoglobin and serum ferritin concentrations (measured in all participants
at baseline and those in the study at 5-year follow-up) were significantly
higher in both groups after 5 years, with no substantial difference between
the groups (R.H., unpublished data, August 2003).
The costs of health care, out-of-pocket costs (ie, medication, travel),
and productivity losses (ie, sick leave days) are provided in Table 2. The discounted total cost per participant was $2817 (95%
confidence interval [CI], $2222-$3530) in the LNG-IUS group and $4660 (95%
CI, $4014-$5180) in the hysterectomy group. Both the discounted direct cost
and the discounted productivity losses (indirect cost) were significantly
lower in the LNG-IUS group vs the hysterectomy group (direct cost: $1892 [95%
CI, $1352-$2189] vs $2787 [95% CI, $2312-$3133], respectively; productivity
losses: $925 [95% CI, $725-$1232] vs $1873 [95% CI, $1650-$2096]). Because
the difference in quality-adjusted life-years showed no statistical difference
between the groups, no incremental cost-utility ratio was calculated.
The robustness of our findings was tested using different estimates
of discount rate, cost of hysterectomy, wage rate, and health care use (visits
to private physicians, Papanicolaou tests, and medications). The sensitivity
analyses showed that these variables had no significant effect on the difference
in cost (Table 3). The serious
adverse events in 2 women in the hysterectomy group caused extra costs due
to 11 inpatient days in the intensive care unit involving suture of the ileum
and 10 inpatient days involving nephrostoma or ureterneocystostomia and oophorectomy.
However, if these costs are distributed among all women in the hysterectomy
group, the net effect is only $128 per woman.
We showed that in the treatment of menorrhagia, the health-related quality-of-life
outcomes associated with the LNG-IUS and hysterectomy were similar. Although
42% of the women assigned to the LNG-IUS group subsequently underwent hysterectomy,
the overall direct and indirect costs after 5 years were still approximately
40% lower in the LNG-IUS group. In general, women were equally satisfied with
the LNG-IUS and with hysterectomy.
All 5 university hospitals in Finland participated in the study. The
drop-out rate was very low (1%), showing high commitment of the participating
women and absence of compliance bias. The characteristics of the study population
did not differ from those in other studies of menorrhagia. Our inclusion criteria
followed general clinical guidelines, suggesting that selection bias was unlikely.
Moreover, the use of different techniques of hysterectomy reflected current
practice in true clinical settings. Although not all women referred for menorrhagia
complaints were included, those not participating either did not provide consent
or were unable to meet the eligibility criteria. We thus suggest that the
study group represents women who were true candidates for both treatment options
and that the findings are generalizable.
The complication rate of hysterectomy was high when compared with register
studies28,29 but in the same range
when compared with cohort studies.30,31 The
LNG-IUS discontinuation rate also was relatively high. However, this is in
line with other recent studies also showing a relatively high discontinuation
rate after 2 years (34%),32 or after 4 to 5
years (50%).33 Success or failure of treatment
with hysterectomy or the LNG-IUS is multifactorial and difficult to predict
in an individual case. Our subanalyses suggest that lower baseline scores
in HRQL predict poorer continuation rate with the LNG-IUS. It is possible
that women in the LNG-IUS group having hysterectomy had lower tolerance for
adverse effects of the LNG-IUS because of psychosocial problems.
There is some controversy as to whether the results of an economic analysis
performed in 1 country can be generalized to other countries. Also, the relative
price of hysterectomy likely correlates with the likelihood of its use as
a treatment choice. We therefore performed sensitivity analyses for discounting
rate, productivity loss, health care use, and cost of hysterectomy. The results
revealed no significant effect on cost, but the higher price of hysterectomy
made use of the LNG-IUS even more attractive. We have also reported the estimates
separately so that readers can judge the relevance of the trial to their local
Randomized health economic trials of menorrhagia are rare. Five reports
from 3 randomized trials have compared costs of endometrial resection vs hysterectomy.6,34-37 These
trials showed that although endometrial resection has less health care cost
than hysterectomy, the cost disparity narrowed over a prolonged follow-up
primarily because of the retreatment of women who underwent endometrial resection.
After 4 months, the cost of resection was 53% of hysterectomy, whereas after
2 and 4 years the costs accounted for 71%37 and
93%,6 respectively. This study is the first
long-term randomized outcomes and cost trial comparing medical and surgical
treatments of menorrhagia. The findings after the first year suggested that
the decision to treat menorrhagia with hysterectomy rather than with the LNG-IUS
was approximately 3 times more expensive.12 After
5 years, treatment with the LNG-IUS was still 40% less expensive than hysterectomy.
It has been suggested that introduction of endometrial ablation has
increased the overall rate of expensive surgical procedures.38 In
England, hysterectomy rates have increased despite the growing popularity
of endometrial ablation.38 In Finland, the
use of endometrial ablation is low but the LNG-IUS is widely accepted (Finnish
Social Insurance Institution, unpublished data, January 2001). The national
hysterectomy rate has declined by about 13% since 1998 (Finnish Hospital Discharge
Register, unpublished data, 2001), suggesting that the use of the LNG-IUS
is already changing clinical practice.
Because menorrhagia is often a reason for seeking medical attention,
it is important to consider the outcomes and costs of various treatment options
to provide the most appropriate care. The LNG-IUS may improve HRQL at relatively
low cost, undoubtedly enhances patient choice, and may reduce surgery-related
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